Natural killer (NK) cells and killer (K) cells mediating antibody-dependent cellular cytotoxicity have been shown to be large granular lymphocytes (LGLs). Studies are proceeding to define the receptors and structures involved in NK recognition. A monoclonal antibody (MoAb) was developed against NK target antigens on K562 cells and that antibody blocked LGL binding and lysis. We also developed an anti-idiotypic antibody (anti-ID) against this MoAb anticipating that it might recognize the NK receptor and aid in its identification. This anti-ID antibody is reactive with an effector cell protein and blocks LGLs binding and target cell lysis. Utilizing this anti-ID, an expression library from CD3- LGL was screened and specific cDNA clones were isolated and sequenced. Based on the predicted protein sequence, the cDNA was found to code for a unique 1016 AA protein that consisted of several distinct structural domains. The NH2- terminal domain was 50% homologous to cyclophilin, a cyclosporin binding protein. This was followed by the idiotype region, a transmembrane domain, and a 367 AA cytoplasmic domain. Studies are presently underway to further characterize and unequivocally demonstrate the receptor nature of this unique gene.